Substituted oxindole derivatives as tyrosine kinase inhibitors

ABSTRACT

The present invention is related to oxindole derivatives of structure (I), compositions containing the same, and methods of use and manufacture of the same. Such compounds generally are useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signaling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation. Such disease states include tumor growth, restenosis, atherosclerosis, pain and thrombosis, In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in cancer therapy and chronic pain indications.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/US01/26423 filed Aug. 23, 2001, which claims priority from60/230,050 filed Sep. 1, 2000.

BACKGROUND OF THE INVENTION

The present invention is related to oxindole derivatives, compositionscontaining the same, and methods of use and manufacture of the same.Such compounds generally are useful pharmacologically as agents in thosedisease states alleviated by the alteration of mitogen activatedsignaling pathways in general, and in particular in the inhibition orantagonism of protein kinases, which pathologically involve aberrantcellular proliferation. Such disease states include tumor growth,restenosis, atherosclerosis, pain and thrombosis. In particular, thepresent invention relates to a series of substituted oxindole compounds,which exhibit Trk family protein tyrosine kinase inhibition, and whichare useful in cancer therapy and chronic pain indications.

Cell growth, differentiation, metabolism and function are very tightlycontrolled in higher eukaryotes. The ability of a cell to rapidly andappropriately respond to the array of external and internal signals itcontinually receives is of critical importance in maintaining a balancebetween these processes (Rozengurt, Current Opinion in Cell Biology1992, 4, 161-5; Wilks, Progress in Growth Factor Research 1990, 2,97-111). The loss of control over cellular regulation can often lead toaberrant cell function or death, often resulting in a disease state inthe parent organism.

The protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function (Hanks, et al., Science1988, 241, 42-52). A partial list of such kinases includes ab1, ATK,bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck,IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros,tie₁, tie₂, TRK,Yes, and Zap70.

One of the most commonly studied pathways involving kinase regulation iscellular signalling from receptors at the cell surface to the nucleus(Crews and Erikson, Cell 1993, 74, 215-7). One example of this pathwayincludes a cascade of kinases in which members of the growth factorreceptor tyrosine kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, theInsulin receptor), deliver signals through phosphorylation to otherkinases such as Src tyrosine kinase, and the Raf, Mek and Erkserine/threonine kinase families (Crews and Erikson, Cell 1993, 74,215-7; Ihle, et al., Trends in Biochemical Sciences 1994, 19, 222-7).Each of these kinases is represented by several family members (Pelechand Sanghera, Trends in Biochemical Sciences 1992, 17, 233-8) which playrelated, but functionally distinct roles. The loss of regulation of thegrowth factor signaling pathway is a frequent occurrence in cancer aswell as other disease states.

A variety of evidence suggests that nerve growth factor (NGF) may be amediator of some persistent pain states, including neuropathic andinflammatory pain. For example: a) NGF is rapidly elevated in inflamedtissues.; b) NGF specific antibodies substantially diminish inflammatoryhypersensitivity; c) injection of NGF into adult rats causes a profoundhypersensitivity to noxious heat and mechanical stimuli; and d) lowlevel administration of recombinant NGF induces hyperalgesia in healthyhumans. NGF produces hyperalgesia through several potential mechanisms.NGF results in the upregulation of peptide neurotransmitters in neuronsthat detect painful stimuli (nociceptors). NGF increases theexcitability of spinal cord neurons to activation. Mast cells expressNGF receptors and NGF triggers the release of granules containinghistamine and serotonin. Histamine and serotonin are capable ofsensitizing nociceptors. (Wood, John (2000) Pathology of Visceral Pain:Molecular Mechanisms and Therapeutic Implications II. Genetic Aproachesto Pain Therapy. Am. J. Physiol. 278(40), G507-G512.)

NGF binds to two different receptors, the neurotrophin receptor p75(p75NTR) and TrkA. p75NTR is a member of a family of receptors thatincludes tumor necrosis factor receptor (TNFR) and FAS/APO1. Thesereceptors have in common a cysteine-rich motif in the extracellulardomain, a single transmembrane domain, and a cytoplasmic domain. p75NTRsignals in a fashion similar to TNFR and FAS via the activation of NFkB,JNK, and ceramide production. The functional significance of p75NTR inNGF mediated biological responses is not clear. Proposed functionsinclude a) modulation of TrkA driven responses and b) induction of celldeath in cells that express p75NTR, but not TrkA.

TrkA appears to be the primary mediator of NGF driven biologicalresponses. The most compelling evidence for this comes from NGF and TrkAknockout mice. Mice defective in either the ligand or receptor componentof this system have remarkably similar phenotypes. Examples of thesephenotypes include severe sensory defects characterized by a completeloss of nociceptive activity and deficiencies in thermoception.Anatomically these mice exhibit extensive peripheral nervous system cellloss in trigeminal, dorsal root, and sympathetic ganglia. Other evidencefor the involvement of TrkA in NGF driven responses comes from the studyof the PC12 cell line. PC12 cells express high levels of p75NTR andTrkA. NGF causes PC12 cells to differentiate into a neuronal phenotypecharacterized by the development of axonal projections. Loss of TrkAprevents PC12 cells from differentiating in response to NGF. (Eggert,A.; Ikegaki, N.; Lui, X.; Chou, T.; Lee, V.; Trojanowski, J. Q.;Brodeur, G. M.; (2000) Molecular Dissection of TrkA Signal TransductionPathways Mediating Differentiation in human Neuroblastoma Cells.Oncogene, 19(16), 2043-2051.)

There is evidence that Trk tyrosine kinases play a role in thedevelopment of a variety of cancers including, for example, breast andprostate cancer. (Guate, J. L. et al, (1999) Expression of p75LNGFR andTrk Neurotrophin Receptors in Normal and Neoplastic Human Prostate, BJUInt 84(4), 495-502; Tagliabue, E. et al, S. Nerve Growth Factorcooperates with p185HER2 in Activating Growth of Human Breast CarcinomaCells, (2000) J. Biol Chem. 275(8), 5388-5394). Further, there is strongevidence that mediation of the Trk kinase signaling will providebeneficial biological effects. (LeSauteur, L. et al, (1998) Developmentand Uses of Small Molecule Ligands of TrkA Receptors, Adv. Behav. Biol.49, 615-625; Zhu, Z. et al, (1999) Nerve Growth Factor ExpressionCorrelates with Perineural Invasion and Pain in Human Pancreatic Cancer,Journal of Clinical Oncology, 17(8), 2419-28; Friess, H et al, NerveGrowth Factor and its High-Affinity Receptor in Chronic Pancreatitis,(1999) Annals of Surgery 230(5), 615-24.)

TrkA is a receptor tyrosine kinase that belongs to a subfamily oftyrosine kinases that includes TrkB, and TrkC. TrkB and TrkC arestructurally similar to TrkA, but respond to different ligands in theneurotrophin family. NGF signaling through TrkA has been bestcharacterized in the PC12 system and is similar to signal transductionmechanisms of other tyrosine kinase receptors. NGF exists as ahomodimer. Binding of NGF promotes dimerization, andautophoshphorylation of TrkA. Phosphorylation of TrkA increases thecatalytic activity of the kinase domain and creates binding sites forSH2 domain containing cytoplasmic proteins. SH2 domain binding eventsinitiate the activation of several signal transduction pathways such asPLCg, ras, PI3 kinase/AKT, and Raf/MEK/ERK. (Frade, J. M. et al (1998)Nerve growth factor: two receptors, multiple functions, BioEssays 20:137-145; Kaplan, D. R. et al, (1997) Signal Transduction by theNeurotrophin Receptors, Current Opinion in Cell Biology. 9: 213-221;Barbacid, M. (1995) Neurotrophic factors and their receptors, CurrentOpinion in Cell Biology. 7:148-155; Snider, W. D. (1994) Functions ofthe Neurotrophins During Nervous System Development: What the Knockoutsare Teaching Us, Cell, 77:627-638.)

The selective inhibition of Trk family of kinases (TrkA, TrkB, and TrkC)is therefore an object of the present invention.

There is a continuing need in the medical field for new and moreeffective treatments for cancer and for the relief of pain, especiallychronic pain. Because TrkA and other Trk kinases may serve as a mediatorof NGF driven biological responses, inhibitors of TrkA and other Trkkinases may provide an effective treatment for cancer and for chronicpain states. At present, there is an unmet need for small moleculecompounds that may be readily synthesized and are potent inhibitors ofTrkA and other Trk family kinases. The present inventors have nowdiscovered novel oxindole derivative compounds that selectively inhibitthe catalytic activity of TrkA and/or other Trk family kinases therebyproviding new treatment strategies for those afflicted with cancer andchronic pain.

It is additionally possible that inhibitors of certain kinases may haveutility in the treatment of diseases when the kinase is notmis-regulated, but is nonetheless essential for maintenance of thedisease state.

SUMMARY OF THE INVENTION

In one aspect the present invention provides, compounds of the formula(I):

wherein

-   X is N, CH, CCF₃, or C(C₁₋₁₂ aliphatic);-   R¹ is hydrogen, C₁₋₁₂ aliphatic, thiol, hydroxy, hydroxy-C₁₋₁₂    aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic, R⁶-Aryl-C₁₋₁₂ aliphatic, Cyc,    Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy,    amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂    aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂    alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R⁶,    Aryl, Cyc and Het are as defined below;-   R² is hydrogen, C₁₋₁₂ aliphatic, N-hydroxyimino-C₁₋₁₂ aliphatic,    C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxycarbonyl,    carboxyl C₁₋₁₂ aliphatic, Aryl, R⁶-Aryl-oxycarbonyl,    R⁶-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₁₂    aliphatic-aminocarbonyl, Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,    R⁶-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl, Het-C₁₋₁₂    aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂ aliphatic-aminocarbonyl,    C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl, C₁₋₁₂ alkoxy-C₁₋₁₂    aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic    aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen, hydroxy,    nitro, C₁₋₁₂ aliphatic-sulfonyl, aminosulfonyl, or C₁₋₁₂    aliphatic-aminosulfonyl, where Aryl and Het are as defined below;-   further wherein R¹ and R² are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    below, or any of said fused rings optionally substituted by C₁₋₁₂    aliphatic, halogen, nitro, cyano, C₁₋₁₂ alkoxy, carbonyl-C₁₋₁₂    alkoxy or oxo;-   R³ is hydrogen, C₁₋₁₂ aliphatic, hydroxy, hydroxy C₁₋₁₂ aliphatic,    di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂    aliphatic aminosulfonyl, C₁₋₁₂ alkoxy, Aryl, Aryloxy, hydroxy-Aryl,    Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as    defined below;-   further wherein R² and R³ are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    below, or any of said fused rings optionally substituted by C₁₋₆    aliphatic or C₁₋₆ aliphatic-carbonyl;-   R⁴ is sulfonic acid, C₁₋₁₂ aliphatic-sulfonyl, sulfonyl-C₁₋₁₂    aliphatic, C₁₋₁₂ aliphatic-sulfonyl-C₁₋₆ aliphatic, C₁₋₆    aliphatic-amino, R⁷-sulfonyl, R⁷-sufonyl-C₁₋₁₂ aliphatic,    R⁷-aminosulfonyl, R⁷-aminosulfonyl-C₁₋₁₂ aliphatic,    R⁷-sulfonylamino, aminosulfonyl-C₁-C₁₂-aliphatic,    R⁷-sulfonylamino-C₁₋₁₂ aliphatic, aminosulfonylamino, di-C₁₋₁₂    aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂    aliphatic aminosulfonyl, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂    aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl-C₁₋₁₂    aliphatic, (R⁸)₁₋₃-Arylamino, (R⁸)₁₋₃-Arylsulfonyl,    (R⁸)₁₋₃-Aryl-aminosulfonyl, (R⁸)₁₋₃-Aryl-sulfonylamino, Het-amino,    Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or    aminoiminoaminosulfonyl, where R⁷, R⁸, Aryl and Het are as defined    below;-   R⁵ is hydrogen;-   and further wherein R⁴ and R⁵ are optionally joined to form a fused    ring, said ring selected from the group as defined for Het below, or    any of said used rings optionally substituted by C₁₋₁₂ aliphatic,    oxo or dioxo;-   R⁶ is C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, or halogen;-   R⁷ is hydrogen, C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ alkoxy,    hydroxy-C₁₋₁₂ aliphatic, carboxylic acid, C₁₋₁₂ aliphatic-carbonyl,    Het, Het-C₁₋₁₂-aliphatic, Het-C₁₋₁₂-alkoxy, di-Het-C₁₋₁₂-alkoxy    Aryl, Aryl-C₁₋₁₂-aliphatic, Aryl-C₁₋₁₂-alkoxy, Aryl-carbonyl, C₁₋₁₈    alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl    are as defined below;-   R⁸ is hydrogen, nitro, cyano, C₁₋₁₂ alkoxy, halo, carbonyl-C₁₋₁₂    alkoxy or halo-C₁₋₁₂ aliphatic;-   Aryl is phenyl, naphthyl, phenanthryl or anthracenyl; Cyc is    cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or    cyclooctyl, any one of which may have one or more degrees of    unsaturation;-   Het is a saturated or unsaturated heteroatom ring system selected    from the group consisting of benzimidazole, dihydrothiophene,    dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole,    dithiolane, furan, imidazole, isoquinoline, morpholine, oxazole,    oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine,    piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine,    pyrimidine, pyrrole, pyrrolidine, quinoline, tetrahydrofuran,    tetrazine, thidiazine, thiadiazole, thiatriazole, thiazine,    thiazole, thiomorpholine, thiophene, thiopyran, triazine and    triazole, with the proviso that when R² is thiadiazine, then R⁴    cannot be methylsulfone;-   and the pharmaceutically acceptable salts, solvates, or    physiologically functional derivatives thereof including    biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable    carbamates solvates, hydrates, affinity reagents or prodrugs thereof    in either crystalline or amorphous form.

In another aspect of the present invention, there is provided compoundsof formula (I):

wherein

-   X is N, CH, or C(C₁₋₆ aliphatic);-   R¹ is hydrogen, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic, Aryl-C₁₋₆    aliphatic, R⁶-Aryl-C₁₋₆ aliphatic, Cyc-C₁₋₆ aliphatic, Het-C₁₋₆    aliphatic, C₁₋₆ alkoxy, Aryloxy, aminocarbonyl, di-C₁₋₆ aliphatic    amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆ aliphatic    aminosulfonyl, C₁₋₆ alkoxycarbonyl, halogen, or nitro, where R⁶,    Aryl, Cyc and Het are as defined below;-   R² is hydrogen, C₁₋₆ aliphatic, R⁷—C₁₋₆ aliphatic, C₁₋₆alkoxy,    hydroxy-C₁₋₆ aliphatic, C₁₋₆ alkoxycarbonyl, carboxyl C₁₋₆    aliphatic, Aryl, R⁶-Aryl-oxycarbonyl, R⁶-oxycarbonyl-Aryl, Het,    aminocarbonyl, C₁₋₆ aliphatic-aminocarbonyl, Aryl-C₁₋₆    aliphatic-aminocarbonyl, R⁶-Aryl-C₁₋₆ aliphatic-aminocarbonyl,    Het-C₁₋₆ aliphatic-aminocarbonyl, hydroxy-C₁₋₆    aliphatic-aminocarbonyl, C₁₋₆-alkoxy-C₁₋₆ aliphatic-aminocarbonyl,    C₁₋₆ alkoxy-C₁₋₆ aliphatic-amino, di-C₁₋₆ aliphatic amino, di-C₁₋₆    aliphatic aminocarbonyl, di-C₁₋₆ aliphatic aminosulfonyl, halogen,    hydroxy, nitro, sulfo, C₁₋₆ aliphatic-sulfonyl, aminosulfonyl, C₁₋₆    aliphatic-aminosulfonyl, or quaternary ammonium, where R⁷, Aryl and    Het are as defined below;-   further wherein R¹ and R² are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    above, or any of said fused rings optionally substituted by halogen    or oxo;-   R³ is hydrogen, C₁₋₆ aliphatic, hydroxy, hydroxy C₁₋₆ aliphatic,    di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆    aliphatic aminosulfonyl, C₁₋₆ alkoxy, Aryl, Aryloxy, hydroxy-Aryl,    Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as    defined below;-   further wherein R² and R³ are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    above, or any of said fused rings optionally substituted by C₁₋₆    aliphatic or C₁₋₆ aliphatic-carbonyl;-   R⁴ is sulfonic acid, C₁₋₁₂ aliphatic-sulfonyl, sulfonyl-C₁₋₁₂    aliphatic, C₁₋₁₂ aliphatic-sulfonyl-C₁₋₆ aliphatic, C₁₋₆    aliphatic-amino, R⁷-sulfonyl, R⁷-sulfonyl-C₁₋₁₂ aliphatic,    R⁷-aminosulfonyl, R⁷-aminosulfonyl-C₁₋₁₂ aliphatic,    R⁷-sulfonylamino, R⁷-sulfonylamino-C₁₋₁₂ aliphatic,    aminosulfonylamino, aminosulfonyl-C₁-C₁₂-aliphatic, di-C₁₋₁₂    aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂    aliphatic aminosulfonyl, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂    aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl-C₁₋₁₂    aliphatic, (R⁸)₁₋₃-Arylamino, (R⁸)₁₋₃-Arylsulfonyl,    (R⁸)₁₋₃-Aryl-aminosulfonyl, (R⁸)₁₋₃-Aryl-sulfonylamino, Het-amino,    Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or    aminoiminoaminosulfonyl, where R⁷, R⁸, Aryl and Het are as defined    below;-   R⁵is hydrogen;-   and further wherein R⁴ and R⁵ are optionally joined to form a fused    ring, said ring selected from the group as defined for Het above, or    any of said used rings optionally substituted by oxo or dioxo;-   R⁶ is hydrogen, C₁₋₆ aliphatic, hydroxy, C₁₋₆ alkoxy, or halogen;-   R⁷ is hydrogen, C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ alkoxy,    hydroxy-C₁₋₁₂ aliphatic, carboxylic acid, C₁₋₁₂ aliphatic-carbonyl,    Het, Het-C₁₋₁₂-aliphatic, Het-C₁₋₁₂-alkoxy, di-Het-C₁₋₁₂-alkoxy    Aryl, Aryl-C₁₋₁₂-aliphatic, Aryl-C₁₋₁₂-alkoxy, Aryl-carbonyl, C₁₋₁₈    alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl    are as defined below;-   R⁸ is hydrogen or halo-C₁₋₆ aliphatic;-   Aryl is phenyl, or naphthyl;-   Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl    or cyclooctyl, any one of which may have one or more degrees of    unsaturation;-   Het is a saturated or unsaturated heteroatom ring system selected    from the group consisting of benzimidazole, dihydrothiophene,    dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole,    dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole,    oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine,    piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine,    pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine,    thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine,    thiophene, thiopyran, triazine and triazole with the proviso that    when R² is thiadiazine, then R⁴ cannot be methylsulfone;-   and the pharmaceutically acceptable salts, solvates, or    physiologically functional derivatives thereof including    biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable    carbamates, solvates, hydrates, affinity reagents or prodrugs    thereof in either crystalline or amorphous form.

In a further aspect of the present invention, there is providedcompounds of formula (I):

wherein

-   X is N, CH, or CCH₃;-   R¹ is hydrogen, C₁₋₆ aliphatic, hydroxy-C₁₋₆ aliphatic, di-C₁₋₆    aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆ aliphatic    aminosulfonyl, Aryl-C₁₋₆ aliphatic, R⁶-Aryl-C₁₋₆ aliphatic, Cyc-C₁₋₆    aliphatic, Het-C₁₋₆ aliphatic, C₁₋₆ alkoxy, Aryloxy, aminocarbonyl,    C₁₋₆ alkoxycarbonyl, halogen, or nitro, where R⁶, Aryl, Cyc and Het    are as defined below;-   R² is hydrogen, C₁₋₆ aliphatic, N-hydroxyimino-C₁₋₆ aliphatic,    C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, Aryl, R⁶-Aryloxycarbonyl, Het,    aminocarbonyl, C₁₋₆ aliphatic aminocarbonyl, Aryl-C₁₋₆ aliphatic    aminocarbonyl, R⁶-Aryl-C₁₋₆ aliphatic aminocarbonyl, Het-C₁₋₆    aliphatic aminocarbonyl, di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphatic    aminocarbonyl, di-C₁₋₆ aliphatic aminosulfonyl, hydroxy-C₁₋₆    aliphatic aminocarbonyl, C₁₋₆-alkoxy-C₁₋₆ aliphatic aminocarbonyl,    C₁₋₆ alkoxy-C₁₋₆ aliphatic amino, halogen, hydroxy, nitro, C₁₋₆    aliphatic sulfonyl, or aminosulfonyl, C₁₋₆ aliphatic aminosulfonyl,    where Aryl and Het are as defined below;-   further wherein R¹ and R² are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    below, or any of said fused rings optionally substituted by halogen    or oxo;-   R³ is hydrogen, C₁₋₆ aliphatic, hydroxy, hydroxy C₁₋₆ aliphatic,    di-C₁₋₆ aliphatic amino, di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆    aliphatic aminosulfonyl C₁₋₆ alkoxy, Aryloxy, Het, or halogen, where    Aryl and Het are as defined below;-   further wherein R² and R³ are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    below, or any of said fused rings optionally substituted by C₁₋₆    alkyl or C₁₋₆ alkylcarbonyl;-   R⁴ is R⁷-sulfonyl, R⁷-sulfonyl C₁₋₆-aliphatic, C₁₋₆ aliphatic    sulfonyl-C₁₋₆ aliphatic, R⁷-aminosulfonyl, di-C₁₋₆ aliphatic amino,    di-C₁₋₆ aliphatic aminocarbonyl, di-C₁₋₆ aliphatic aminosulfonyl,    di-C₁₋₆ aliphatic aminosulfonyl-C₁₋₆ aliphatic,    aminosulfonyl-C₁-C₁₂-aliphatic, R⁷-aminosulfonyl C₁₋₆ aliphatic,    aminosulfonylamino, R⁷—C₁₋₆ aliphatic aminosulfonyl-C₁₋₆ aliphatic,    Aryl, Het, R⁸-Aryl-aminosulfonyl, Het-aminosulfonyl, or    aminoiminoaminosulfonyl, where R⁷, R⁸, Aryl and Het are as defined    below;-   R⁵ is hydrogen;-   and further wherein R⁴ and R⁵ are optionally joined to form a fused    ring, said ring selected from the group as defined for Het below, or    any of said used rings optionally substituted by oxo or dioxo;-   R⁶ is hydroxy, C₁₋₆ alkoxy, or halogen;-   R⁷ is hydrogen, C₁₋₆ aliphatic, hydroxy C₁₋₆-alkoxy, hydroxy-C₁₋₆    aliphatic, C₁₋₆ aliphatic carbonyl, Aryl-carbonyl, C₁₋₁₂    alkoxyalkoxyalkoxyalkoxyalkyl, hydroxyl, Aryl, Aryl-C₁₋₆-alkoxy,    Aryl-C₁₋₆-aliphatic, Het, Het-C₁₋₆-alkoxy, di-Het-C₁₋₆-alkoxy,    Het-C₁₋₆-alkoxy, Het-C₁₋₆-aliphatic, di-Het-C₁₋₆-aliphatic;-   R⁸ is trifluoromethyl;-   Aryl is phenyl;-   Cyc is cyclobutyl;-   Het is a saturated or unsaturated heteroatom ring system selected    from the group consisting of benzimidazole, dihydrothiophene,    dioxolane, furan, imidazole, morpholine, oxazole, pyridine, pyrrole,    pyrrolidine, thiadiazole, thiazole, thiophene, and triazole, with    the proviso that when R² is thiadiazine, then R⁴ cannot be    methylsulfone;-   and the pharmaceutically acceptable salts, solvates, physiologically    functional derivatives thereof, including biohydrolyzable esters,    biohydrolyzable amides, biohydrolyzable carbamates, solvates,    hydrates, affinity reagents or prodrugs thereof in either    crystalline or amorphous form.

In a still further aspect of the present invention, there is providedcompounds of formula (I):

wherein

-   X is CH;-   R¹ is hydrogen, C₁₋₁₂ aliphatic, thiol, hydroxy, hydroxy-C₁₋₁₂    aliphatic, Aryl, Aryl-C₁₋₁₂ aliphatic, R⁶-Aryl-C₁₋₁₂ aliphatic, Cyc,    Cyc-C₁₋₆ aliphatic, Het, Het-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, Aryloxy,    amino, C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂    aliphatic aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, C₁₋₁₂    alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R⁶,    Aryl, Cyc and Het are as defined below;-   R² is hydrogen, C₁₋₁₂ aliphatic, N-hydroxyimino-C₁₋₁₂ aliphatic,    C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxycarbonyl,    carboxyl C₁₋₁₂ aliphatic, Aryl, R⁶-Aryl-oxycarbonyl,    R⁶-oxycarbonyl-Aryl, Het, aminocarbonyl, C₁₋₁₂    aliphatic-aminocarbonyl, Aryl-C₁₋₁₂ aliphatic-aminocarbonyl,    R⁶-Aryl-C₁₋₁₂ aliphatic-aminocarbonyl, Het-C₁₋₁₂    aliphatic-aminocarbonyl, hydroxy-C₁₋₁₂ aliphatic-aminocarbonyl,    C₁₋₁₂-alkoxy-C₁₋₁₂ aliphatic-aminocarbonyl, C₁₋₁₂ alkoxy-C₁₋₁₂    aliphatic-amino, di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic    aminocarbonyl, di-C₁₋₁₂ aliphatic aminosulfonyl, halogen, hydroxy,    nitro, C₁₋₁₂ aliphatic-sulfonyl, aminosulfonyl, or C₁₋₁₂    aliphatic-aminosulfonyl, where Aryl and Het are as defined below;-   further wherein R¹ and R² are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    below, or any of said fused rings optionally substituted by halogen,    nitro, cyano, C₁₋₁₂ alkoxy, carbonyl-C₁₋₁₂ alkoxy or oxo;-   R³ is hydrogen, C₁₋₁₂ aliphatic, hydroxy, hydroxy C₁₋₁₂ aliphatic,    di-C₁₋₁₂ aliphatic amino, di-C₁₋₁₂ aliphatic aminocarbonyl, di-C₁₋₁₂    aliphatic aminosulfonyl, C₁₋₁₂ alkoxy, Aryl, Aryloxy, hydroxy-Aryl,    Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as    defined below;-   further wherein R² and R³ are optionally joined to form a fused    ring, said fused ring selected from the group as defined for Het    below, or any of said fused rings optionally substituted by C₁₋₆    aliphatic or C₁₋₆ aliphatic-carbonyl;-   R⁴ is R⁷-aminosulfonyl, R⁷-aminosulfonyl-C₁₋₁₂ aliphatic,    R⁷-sulfonylamino, R⁷-sulfonylamino-C₁₋₁₂ aliphatic,    aminosulfonylamino, di-C₁₋₁₂ aliphatic aminosulfonyl, di-C₁₋₁₂    aliphatic aminosuIfonyl-C₁₋₁₂ aliphatic, (R⁸)₁₋₃-Aryl-aminosuIfonyl,    aminosulfonyl-C₁-C₁₂-aliphatic,-   (R⁸)₁₋₃-Aryl-sulfonylamino, or aminoiminoaminosulfonyl, where R⁷,    R⁸, Aryl and Het are as defined below;-   R⁵ is hydrogen;-   R⁶ is C₁₋₁₂ aliphatic, hydroxy, C₁₋₁₂ alkoxy, or halogen;-   R⁷ is hydrogen, C₁₋₁₂ aliphatic, C₁₋₁₂ alkoxy, hydroxy-C₁₋₁₂ alkoxy,    hydroxy-C₁₋₁₂ aliphatic, carboxylic acid, C₁₋₁₂ aliphatic-carbonyl,    Het, Het-C₁₋₁₂-aliphatic, Het-C₁₋₁₂-alkoxy, di-Het-C₁₋₁₂-alkoxy    Aryl, Aryl-C₁₋₁₂-aliphatic, Aryl-C₁₋₁₂-alkoxy, Aryl-carbonyl, C₁₋₁₈    alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl    are as defined below;-   R⁸ is hydrogen, nitro, cyano, C₁₋₁₂ alkoxy, halo, carbonyl-C₁₋₁₂    alkoxy or halo-C₁₋₁₂ aliphatic;-   Aryl is phenyl, naphthyl, phenanthryl or anthracenyl;-   Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl    or cyclooctyl, any one of which may have one or more degrees of    unsaturation;-   Het is a saturated or unsaturated heteroatom ring system selected    from the group consisting of benzimidazole, dihydrothiophene,    dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole,    dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole,    oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine,    piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine,    pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine,    thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine,    thiophene, thiopyran, triazine and triazole with the proviso that    when R² is thiadiazine, then R⁴ cannot be methylsulfone;-   and the pharmaceutically acceptable salts, solvates, physiologically    functional derivatives thereof, including biohydrolyzable esters,    biohydrolyzable amides, biohydrolyzable carbamates solvates,    hydrates, affinity reagents or prodrugs thereof in either    crystalline or amorphous form.

In another aspect of the present invention, there is provided a compoundof the formula I, or salts, solvates, or physiological functionalderivatives thereof

wherein:

-   R¹ is hydrogen or halogen;-   R² is hydrogen, hydroxy or methoxy;-   R³ is hydrogen or C₁-C₆ branched alkyl;-   R⁴ is selected from the group consisting of-   R⁵ is hydrogen; and-   X is N or CH.

Due to the presence of an oxindole exocyclic double bond, also includedin the compounds of the invention are their respective pure E and Zgeometric isomers as well as mixtures of E and Z isomers. The inventionas described and claimed does not set any limiting ratios on prevalenceof Z to E isomers. Thus compound number 104 in the tables below isdisclosed and claimed as the E geometric thereof, the Z geometric isomerthereof and a mixture of the E and Z geometric isomers thereof, but notlimited by any given ratio(s).

Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula.

Certain of the compounds as described will contain one or more chiral,or asymmetric, centers and will therefore be capable of existing asoptical isomers that are either dextrorotatory or levorotatory. Alsoincluded in the compounds of the invention are the respectivedextrorotatory or levorotatory pure preparations, and mixtures thereof.

Certain compounds of formula (I) above may exist in stereoisomeric forms(e.g. they may contain one or more asymmetric carbon atoms or mayexhibit cis-trans isomerism). The individual stereoisomers (enantiomersand diastereoisomers) and mixtures of these are included within thescope of the present invention. Likewise, it is understood thatcompounds of formula (I) may exist in tautomeric forms other than thatshown in the formula and these are also included within the scope of thepresent invention.

A further aspect of the invention provides a method of treating adisorder in a mammal, said disorder mediated by inappropriate mitogenactivated kinase activity, including administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate, or physiologically functional derivative thereof. In oneembodiment, the disorder is cancer. In another embodiment the disorderis chronic pain. In a further embodiment, the disorder involves abnormalangiogenesis, such as arthritis, diabetic retinopathy, maculardegeneration and psoriasis.

In a related aspect the present invention comprises a method forinhibiting a kinase comprising bringing said kinase into contact with acompound of formula (I), or a salt, solvate, or physiologicallyfunctional derivative thereof.

Another aspect of the present invention provides for the use of acompound of formula (I), or a salt, solvate, or physiologicallyfunctional derivative thereof, in the preparation of a medicament forthe treatment of a disorder mediated by inappropriate TrkA activity. Inone embodiment, the disorder is cancer. In another embodiment, thedisorder is chronic pain. In a further embodiment, the disorder involvesabnormal angiogenesis, such as arthritis, diabetic retinopathy, maculardegeneration and psoriasis.

Additionally, compounds of formula (I) or salts, solvates, orphysiologically functional derivatives thereof, can be used in thepreparation of a medicament for the treatment of organ transplantrejection, tumor growth, chemotherapy-induced mucositis,radiation-induced mucositis, plantar-palmar syndrome,chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia,chemotherapy-induced leukopenia and hirsutism or of treating a diseasestate selected from the group consisting of: mucocitis, restenosis,atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis,glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,chronic obstructive pulmonary disease, thrombotic microangiopathy,aglomerulopathy, psoriasis, diabetes mellitus, inflammation, aneurodegenerative disease, macular degeneration, actinic keratosis andhyperproliferative disorders.

Another aspect of the present invention provides the use of an activecompound of formula (I), in co-administration or alternatingadministration with previously known anti-tumor therapies for moreeffective treatment of such tumors.

Other aspects of the present invention related to the inhibition ofprotein kinases are discussed in more detail below.

The inappropriate TrkA activity referred to herein is any TrkA activitythat deviates from the normal TrkA activity expected in a particularmammalian subject. Inappropriate TrkA activity may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of TrkA activity. Such inappropriate activity mayresult then, for example, from overexpression or mutation of the proteinkinase leading to inappropriate or uncontrolled activation. Furthermore,it is also understood that unwanted TrkA activity may reside in anabnormal source, such as a malignancy. That is, the level of TrkAactivity does not have to be abnormal to be considered inappropriate,rather the activity derives from an abnormal source.

Compounds we have synthesized as part of the present invention which arecurrently preferred are listed in Tables 1 and 2 below. Compounds areidentified by the numbers shown in the first column; variables below inthe rest of the columns are with reference to the generic structure (I).Corresponding IUPAC nomenclature are disclosed in Table 2. Since allsubstituents at each point of substitution are capable of independentsynthesis of each other, the tables are to be read as a matrix in whichany combination of substituents is within the scope of the disclosureand claims of the invention.

TABLE 1 (I)

Example R¹ R² R³ R⁴ R⁵ X 1 Cl OH i-propyl 4′-CH₂—SO₂NHCH₃ H N 2 —H H H4′-NHSO₂CH₃ H CH 3 —H H H

H CH 4 —H H H

H CH 5 —H H H 3′-SO₂NH₂ H CH

Standard accepted nomenclature corresponding to the Examples set forthin this specification are set forth below. In some cases nomenclature isgiven for one or more possible isomers.

TABLE II Example 1:{4-[(2Z)-2-(4-chloro-5-hydroxy-6-isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]phenyl}-N- methylmethanesulfonamideExample 2: N-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)methanesulfonamide Example 3:4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-amino}-N-(2-pyridinyl)benzenesulfonamide Example 4:N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}- benzenesulfonamide Example 5:3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

The invention discloses six different points of substitution onstructural formula (I). Each of these points of substitution bears asubstituent whose selection and synthesis as part of this invention wasindependent of all other points of substitution on formula (I). Thus,each point of substitution is now further described individually.

Preferred substitutions at the R¹ position include hydrogen, halogen,amide, nitro, lower alkyl, hydroxy, hydroxyalkyl, pyrimidineloweralkyl,loweralkoxycarbonyl, cyclic loweralkyl, hydroxyphenylloweralkyl,phenoxy, alkoxy, or pyrazole, or are fused with R² to form fusedthiazole, pyrazole, triazole, halogen-substituted diazole, acylsubstituted pyrrole, and pyridine, rings. Most preferred are hydrogen,halogen, methyl and fused with R² for form fused thiazole and fusedpyridine. Most highly preferred are halogen and hydrogen.

Preferred substitutions at the R² position include hydrogen, halogen,hydroxyl, sulfate, amine, quaternary amine, amide, ester, phenyl,alkoxy, aminosulfonyl, lower alkyl sulfonyl, furanyl lower alkyl amide,pyridinyl lower alkyl amide, alkoxy-substituted phenyl lower alkylamide, morpholino lower alkyl amide, imidazolyl lower alkyl amide,hydroxy lower alkyl amide, alkoxy lower alkyl amide, lower alkyl amide,lower alkyl sulfonamide, lower alkyl hydroxy substituted amino, nitro,halogen-substituted phenoxycarbonyl, or triazole or oxazole rings, orare fused with R³ to form a fused oxazole, pyrrole, or dioxolane ring,which fused rings can be substituted by lower alkyl, lower alkylcarbonyl, or, when said fused ring is a hetero ring having nitrogen asthe heteroatom, forming a quaternary ammonium salt ionically bonded witha halogen atom. Most preferred are hydrogen, hydroxyl, oxazolyl, loweralkoxy, or fused with R¹ to form fused thiazolyl or fused pyridyl Mosthighly preferred are hydroxy, methoxy and hydrogen.

Preferred substitutions at R³ include hydrogen, lower alkyl, hydroxylower alkyl, halogen, phenoxy, and alkoxy. Most preferred are hydrogenand branched lower alkyl. Most highly preferred is hydrogen andisopropyl.

Preferred substitutions at R⁴ include sulfonylamino, sulfonylaminoamino,lower alkyl sulfonylamino, lower alkylsulfonyl lower alkyl,alkoxysulfonylamino, phenylcarbonylsulfonylamino, phenoxysulfonyl,hydroxy lower alkylsulfonylamino, hydroxy lower alkylsulfonylamino loweralkyl, alkyl, phenylsulfonylamino, optionally substituted by halogensubstituted lower alkyl, aminoiminosulfonylamino,alkylsulfonylaminoalkyl, pyridinyl lower alkyl sulfonylamino,benzamideazolesulfonylamino, pyridylsulfonylamino,pyrimidinylsulfonylamino, thiadiazolylsulfonylamino optionallysubstituted by lower alkyl, thiazolesulfonylamino,-aminosulfonyl-C-C₁₂-aliphatic, hydroxyalkoxyalkylsulfonylamino, or thegroup 4′-SO₂NH[(CH₂)₂O]₄CH₃, or are fused with R⁵ to form a fusedimidazole, triazole, cyclic sulfonylamino or thiaphene ring optionallydisubstituted on the sulfur heteroatom by oxo. The most preferredsubstitutions are 2 pyridine sulfonylamino, 4 pyridine sulfonylamino,hydroxy n-butyl sulfonylamino, methylsulfonylaminomethylene,sulfonyldimethylamino, fused 1, 2, 3-triazole, and sulfonylamino. Mosthighly preferred is 2 pyridine sulfonylamino, 4 pyridine sulfonylaminoand hydroxy n-butyl sulfonylamino. In an alternate highly preferredembodiment, R4 is 4′-CH₂—SO₂NHCH₃, 4′-NHSO₂CH₃,

or 3′-SO₂NH₂.

The preferred substitution at R⁵ is hydrogen.

Preferred substitutions at X include N, CH, and CCH₃. Most preferred isN and CH.

Preferred individual compounds of the present invention include any oneof the following compounds:

DETAILED DESCRIPTION OF THE INVENTION

Salts encompassed within the term “pharmaceutically acceptable salts”refer to non-toxic salts of the compounds of this invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid or by reacting the acid with a suitable organic orinorganic base. Representative salts include the following salts:Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,Clavulanate, Citrate, Diethanolamine, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Metaphosphoric, Methylbromide, Methylnitrate, Methylsulfate,Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine,Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Trifluoroacetate, Triethiodide, Trimethylammonium and Valerate.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of formula (I) and these form a furtheraspect of the invention.

Also included within the scope of the invention are the individualisomers of the compounds represented by formula (I) above as well as anywholly or partially equilibrated mixtures thereof. The present inventionalso covers the individual isomers of the compounds represented byformula above as mixtures with isomers thereof in which one or morechiral asymmetric centers are inverted.

As used herein, the term “aliphatic” refers to the terms alkyl,alkylene, alkenyl, alkenylene, alkynyl, and alkynylene.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Examples of “alkyl” as used herein include, but are not limitedto, n-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon double bonds, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkenylene”as used herein include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbarnoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon triple bonds, optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkynylene”as used herein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, the term “cycloaliphatic” refers to the termscycloalkyl, cycloalkylene, cycloalkenyl, cycloalkenylene, cycloalkynyland cycloalkylnylene.

As used herein, “cycloalkyl” refers to a alicyclic hydrocarbon groupwith one or more degrees of unsaturation, having from three to twelvecarton atoms, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl, and the like.

As used herein, the term “cycloalkylene” refers to an non-aromaticalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “cycloalkenyl” refers to a substitutedalicyclic hydrocarbon radical having from three to twelve carbon atomsand at least one carbon-carbon double bond in the ring system,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 1-cyclopentene-3-yl,1-cyclohexene-3-yl, 1-cycloheptene-4-yl, and the like.

As used herein, the term “cycloalkenylene” refers to a substitutedalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms and at least one carbon-carbon double bond in the ringsystem, optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 4,5-cyclopentene-1,3-diyl,3,4-cyclohexene-1,1-diyl, and the like.

As used herein, the term “heteroatom ring system” refers to the termsheterocyclic, heterocyclyl, heteroaryl, and heteroarylene. Non-limitingexamples of such heteroatom ring systems are recited in the Summary ofthe Invention, above.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic ring having one ormore degrees of unsaturation containing one or more heteroatomicsubstitutions selected from S, SO, SO₂, O, or N, optionally substitutedwith substituents selected from the group consisting of lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halogen, or lowerperfluoroalkyl, multiple degrees of substitution being allowed. Such aring may be optionally fused to one or more of another “heterocyclic”ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” include, butare not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane,piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” refers to a three totwelve-membered heterocyclic ring diradical having one or more degreesof unsaturation containing one or more heteroatonis selected from S, SO,SO₂, O, or N, optionally substituted with substituents selected from thegroup consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more benzene rings or to one or more of another “heterocyclic” ringsor cycloalkyl rings. Examples of “heterocyclylene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, and the like.

As used herein, the term “aryl” refers to a benzene ring or to anoptionally substituted benzene ring system fused to one or moreoptionally substituted benzene rings to form anthracene, phenanthrene,or napthalene ring systems, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxyearbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of aryl include, but are not limited to, phenyl,2-naphthyl, 1-naphthyl, biphenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited to,benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic heterocyclic aromaticring, containing one or more nitrogen, oxygen, or sulfur heteroatoms atany position, where N-oxides and sulfur monoxides and sulfur dioxidesare permissible heteroaromatic substitutions, optionally substitutedwith substituents selected from the group consisting of lower alkyl,lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano,halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systems, one ormore of the rings may contain one or more heteroatoms. Examples of“heteroaryl” used herein are furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole, andindazole, and the like.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. For polycyclicaromatic ring system diradicals, one or more of the rings may containone or more heteroatoms. Examples of “heteroarylene” used herein arefuran-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is aliphatic.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is aliphatic.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is aliphatic.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is aliphatic.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is aliphatic, cycloaliphatic, or heterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is aliphatic.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aliphatic, cycloaliphatic, or heterocyclyl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both conditions.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above-defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

As used herein, the term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I)) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Solvents may be, by way of example, water, ethanol, or acetic acid.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.Included within the scope of the term are the terms “biohydrolyzablecarbonate”, “biohydrolyzable ureide”, “biohydrolyzable carbamate”,“biohydrolyzable ester”, and “biohydrolyzable amide”.

As used herein, the terms “biohydrolyzable carbonate”, “biohydrolyzableureide” and “biohydrolyzable carbamate” is a carbonate, ureide, orcarbamate, respectively of a drug substance (in this invention, acompound of general formula (I) which either a) does not interfere withthe biological activity of the parent substance but confers on thatsubstance advantageous properties in vivo such as duration of action,onset of action, and the like, or b) is biologically inactive but isreadily converted in vivo by the subject to the biologically activeprinciple. The advantage is that, for example, the biohydrolyzablecarbamate is orally absorbed from the gut and is transformed to (I) inplasma. Many examples of such are known in the art and include by way ofexample lower alkyl carbamates.

As used herein, the term “biohydrolyzable ester” is an ester of a drugsubstance (in this invention, a compound of general formula (I) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable ester is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl esters, lower acyloxy-alkylesters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylacylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” is an amide of a drugsubstance (in this invention, a compound of general formula (I) whicheither a) does not interfere with the biological activity of the parentsubstance but confers on that substance advantageous properties in vivosuch as duration of action, onset of action, and the like, or b) isbiologically inactive but is readily converted in vivo by the subject tothe biologically active principle. The advantage is that, for example,the biohydrolyzable amide is orally absorbed from the gut and istransformed to (I) in plasma. Many examples of such are known in the artand include by way of example lower alkyl amides, α-amino acid amides,alkoxyacyl amides, and alkylaiminoalkylcarbonyl amides.

As used herein, the term “prodrug” includes biohydrolyzable amides,biohydrolyzable esters and biohydrolyzable carbamates and alsoencompasses a) compounds in which the biohydrolyzable functionality insuch a prodrug is encompassed in the compound of formula (I): forexample, a lactam formed by a carboxylic group in R₁ and an amine in R₂,and compounds which may be oxidized or reduced biologically at a givenfunctional group to yield drug substances of formula (I). Examples ofthese functional groups are, but are not limited to,1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,1,4-cyclohexadiene, tert-butyl, and the like.

As used herein, the term “affinity reagent” is a group attached to thecompound of formula (I) which does not affect its in vitro biologicalactivity, allowing the compound to bind to a target, yet such a groupbinds strongly to a third component allowing a) characterization of thetarget as to localization within a cell or other organism component,perhaps by visualization by fluorescence or radiography, or b) facileseparation of the target from an unknown mixture of targets, whetherproteinaceous or not proteinaceous. An example of an affinity reagentaccording to b) would be biotin either directly attached to (I) orlinked with a spacer of one to 50 atoms selected from the groupconsisting of C, H, O, N, S, or P in any combination. An example of anaffinity reagent according to a) above would be fluorescein, eitherdirectly attached to (I) or linked with a spacer of one to 50 atomsselected from the group consisting of C, H, O, N, S, or P in anycombination.

The term “effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher or clinician. The term “therapeutically effective amount”means any amount which, as compared to a corresponding subject who hasnot received such amount, results in improved treatment, healing,prevention, or amelioration of a disease or disorder, or a decrease inthe rate of advancement of a disease or disorder, and also includesamounts effective to enhance normal physiological function.

Whenever the terms “aliphatic” or “aryl” or either of their prefixesappear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall beinterpreted as including those limitations given above for “aliphatic”and “aryl”. Aliphatic or cycloalkyl substituents shall be recognized asbeing term equivalents to those having one or more degrees ofunsaturation. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shallrefer independently to the number of carbon atoms in an aliphatic orcyclic aliphatic moiety or to the aliphatic portion of a largersubstituent in which the term “aliphatic” appears as a prefix (e.g.“al-”).

As used herein, the term “disubstituted amine” or “disubstituted amino-”shall be interpreted to include either one or two substitutions on thatparticular nitrogen atom.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” shall include iodine,bromine, chlorine and fluorine.

As used herein, the term “mercapto” shall refer to the substituent —SH.

As used herein, the term “carboxy” shall refer to the substituent —COOH.

As used herein, the term “cyano” shall refer to the substituent —CN.

As used herein, the term “aminosulfonyl” shall refer to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” shall refer to the substituent—C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the substituent —S—.

As used herein, the term “sulfenyl” shall refer to the substituent—S(O)—.

As used herein, the term “sulfonyl” shall refer to the substituent—S(O)₂—.

PHARMACEUTICAL FORMULATION AND DOSES

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula I, as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions which include therapeutically effectiveamounts of compounds of the formula I and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula I and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula I, or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

The compounds of the present invention can be administered in such oral(including buccal and sublingual) dosage forms as tablets, capsules(each including timed release and sustained release formulations),pills, powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. Likewise, they may also be administered in nasal, ophthalmic,otic, rectal, topical, intravenous (both bolus and infusion),intraperitoneal, intraarticular, subcutaneous or intramuscularinhalation or insufflation form, all using forms well known to those ofordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.1 to 100 mg/kg of body weight perday, and particularly 1 to 10 mg/kg of body weight per day. Oral dosageunits will generally be administered in the range of from 1 to about 250mg and more preferably from about 25 to 250 mg. The daily dosage for a70 kg mammal will generally be in the range of about 70 mg to 7 grams ofa compound of formula I or II.

While the dosage to be administered is based on the usual conditionssuch as the physical condition of the patient, age, body weight, pastmedical history, route of administrations, severity of the conditionsand the like, it is generally preferred for oral administration toadminister to a human. In some cases, a lower dose is sufficient and, insome cases, a higher dose or more doses may be necessary. Topicalapplication similarly may be once or more than once per day dependingupon the usual medical considerations. Advantageously, compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. The compounds of the invention can be prepared in arange of concentrations for topical use of 0.5 to 5 mg/ml of suitablesolvent. A preferred volume for application to the scalp is 2 ml,resulting in an effective dosage delivered to the patient of 1 to 10 mg.For treatment of chemotherapy-induced alopecia, administration 1 to 2times prior to chemotherapy administration would be preferred, withadditional applications administered as needed. A similar regimen can bepursued for treatment of alopecia induced by radiation therapy.Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

The present invention includes pharmaceutical compositions containing0.01 to 99.5%, more particularly, 0.5 to 90% of a compound of theformula (II) in combination with a pharmaceutically acceptable carrier.

Parenteral administration can be effected by utilizing liquid dosageunit forms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as aqueousoleaginous medium and sterilizing the suspension or solution.

Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservations and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher ester as forexample flavored aqueous solution, while elixirs are prepared throughmyristyl palmitate or mixtures thereof.

Topical formulations of the present invention may be presented as, forinstance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams. The formulations mayalso contain compatible conventional carriers, such as cream or ointmentbases and ethanol or oleyl alcohol for lotions. Such carriers may bepresent as from about 1% up to about 98% of the formulation. Moreusually they will form up to about 80% of the formulation.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane,heptafluoropropane, carbon dioxide or other suitable gas. In the case ofa pressurized aerosol the dosage unit may be determined by providing avalve to deliver a metered amount. Capsules and cartridges of e.g.gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of a compound of the invention and a suitablepowder base such as lactose or starch.

The preferred pharmaceutical compositions are those in a form suitablefor oral administration, such as tablets and liquids and the like andtopical formulations.

The compounds of formula (I) can be prepared readily according to thefollowing reaction General Synthesis Scheme (in which all variables areas defined before) and Examples or modifications thereof using readilyavailable starting materials, reagents and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants which are themselves known to those of ordinary skill in thisart, but are not mentioned in greater detail.

The most preferred compounds of the invention are any or all of thosespecifically set forth in these examples. These compounds are not,however, to be construed as forming the only genus that is considered asthe invention, and any combination of the compounds or their moietiesmay itself form a genus. The following examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are degreesCelsius unless noted otherwise.

Abbreviations used in the Examples are as follows:

g = grams mg = milligrams L = liters mL = milliliters M = molar N =normal mM = millimolar i.v. = intravenous p.o. = per oral s.c. =subcutaneous Hz = hertz mol = moles mmol = millimoles mbar = millibarpsi = pounds per square inch rt = room temperature min = minutes h =hours mp = melting point TLC = thin layer chromatography R_(f) =relative TLC mobility MS = mass spectrometry NMR = nuclear magneticresonance spectroscopy APCI = atmospheric pressure chemical ionizationESI = electrospray ionization m/z = mass to charge ratio t_(r) =retention time Pd/C = palladium on activated carbon ether = diethylether MeOH = methanol EtOAc = ethyl acetate TEA = triethylamine DIEA =diisopropylethylamine THF = tetrahydrofuran DMF = N,N-dimethylformamideDMSO = dimethylsulfoxide DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinoneLAH = lithium aluminum hydride TFA = trifluoroacetic acid LDA = lithiumdiisopropylamide THP = tetrahydropyranyl NMM =N-methylmorpholine,4-methylmorpholine HMPA = hexamethylphosphorictriamide DMPU = 1,3-dimethypropylene urea d = days ppm = parts permillion kD = kiloDalton LPS = lipopolysaccharide PMA = phorbol myristateacetate SPA = scintillation proximity assay EDTA = ethylenediaminetetraacetic acid FBS = fetal bovine serum PBS = phosphate bufferedsaline solution BrdU = bromodeoxyuridine BSA = bovine serum albumin FCS= fetal calf serum DMEM = Dulbecco's modified Eagle's medium pfu =plaque forming units MOI = multiplicity of infection

Reagents are commercially available or are prepared according toprocedures in the literature. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds. ¹H NMR spectra were obtained on VARIAN Unity Plus NMRspectrophotometers at 300 or 400 Mhz. Mass spectra were obtained onMicromass Platform II mass spectrometers from Micromass Ltd. Altrincham,UK, using either Atmospheric Chemical Ionization (APCI) or ElectrosprayIonization (ESI). Analytical thin layer chromatography (TLC) was used toverify the purity of some intermediates which could not be isolated orwhich were too unstable for full characterisation, and to follow theprogress of reactions. Unless otherwise stated, this was done usingsilica gel (Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds, used Merck Silicagel 60 (230-400 mesh), and the stated solvent system under pressure.

General Procedures:

Procedure A—Representative Method for 1H-indol-2,3-dione (isatin)formation: Preparation of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione.

To a 1-L flask was added a magnetic stir bar, 85 g of sodium sulfate,and 100 mL of water. The mixture was magnetically stirred until all thesolids were dissolved. To the resultant aqueous solution was added asolution of 6-aminobenzothiazole (4.96 g, 33.0 mmol) in 50 mL of 1Naqueous hydrochloric acid and 10 mL of ethanol. The mixture was stirred,and chloral (6.0 g, (36 mmol) was added. To the resultant solution wasadded a solution of hydroxyl amine hydrochloride (7.50 g, 108 mmol) in30 mL of water. The final mixture was heated with stirring to a gentleboil until all solids dissappeared, and heating was continued for anadditional 15 min. The flask was removed from the heat, and the solutionwas poured onto 500 g of ice. The mixture was stirred as the productprecipatated from solution. The precipatate was collected by suctionfiltration, washed thoroughly with water, filtered, and air dried toprovide 6.9 g (94%) of N-benzothiazol-6-yl-2-hydroxyimino-acetamide: ¹HNMR (DMSO-d₆): δ12.2 (s, 1H), 10.4 (s, 1H), 9.2 (s, 1H), 8.5 (s, 1H),7.9 (d, 1H), 7.7 (m, 1H), 7.7 (s, 1H); APCI-MS m/z 220 (M−H)⁻. To a 1-L3-neck round bottom flask was placed a magnetic stir bar and 100 ml ofconcentrated sulfuric acid. The flask was fitted with a thermometer tomonitor the temperature of the reaction. The sulfuric acid was heated to100° C., and 10.0 g (45.2 mmol) ofN-benzothiazol-6-yl-2-hydroxyimino-acetamide was added slowly. Thesolution was heated for ˜1 h, and the reaction mixture was poured into750 g of ice and water. The residual reaction mixture in the reactionvessel was washed out with an additional 20 mL of cold water. Theaqueous slurry was stirred for about 1 h and filtered. The solid waswashed thoroughly with water, filtered, and air dried to yield 4.3 g(46%) of 6-H-1-thia-3,6-diaza-as-indacen-7,8-dione: ¹H NMR(DMSO-d₆):11.1 (s, 1H), 9.2 (s, 1H), 8.2 (d, 1H), 7.0 (d, 1H); APCI-MSm/z 203 (M−H)⁻.

EXAMPLE 1 Preparation of{4-[(2Z)-2-(4-chloro-5-hydroxy-6-isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]phenyl}-N-methylmethanesulfonamide

4-Chloro-5-hydroxy-6-I-propyl-1H-indole-2,3-dione was prepared from3-chloro-4-hydroxy-5-I-propylaniline according to Procedure A.Condensation of 4-chloro-5-hydroxy-6-I-propyl-1H-indole-2,3-dione (1equivalent) with 4-hydrazino-N-methyl-benzylsulfonamide (1.1 equivalent)was heated in EtOH to 80 C. for 1 h. Upon cooling H₂O was added and thesolid was collected by vacuum filtration and dried in a vacuum oven at60 C to afford the title compound. Electrospray MS 436 (MH⁺).

EXAMPLE 2 Preparation ofN-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)methanesulfonamide

The title compound was prepared analogous to Example 5 from3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one (0.164 g, 1.02 mmol) andN-(4-aminophenyl)-methanesulfonamide [53250-82-1, 0.186 g, 1.0 mmol] toprovide a yellow solid (0.249 g). 1H NMR (DMSO) 10.67 (d, 1H); 10.45 (s,1H); 9.56 (s, 1H); 8.50 (d, 1H); 7.52 (d, 1H); 7.35 (d, 2H); 7.18 (d,2H); 6.95 (m, 1H); 6.89 (m, 1H); 6.80 (m, 1H); 2.92 (s, 3H). MP>250.APCI (−ve) 328. Analytical Calculated for C₁₆H₁₅N₃O₃S: C, 58.35; H,4.59; N, 12.76; S, 9.73. Found: C, 58.40; H, 4.63; N, 12.75; S, 9.63.

EXAMPLE 3 Preparation of 4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}-N-(2-pyridinyl)benzenesulfonamide

The title compound was prepared analogous to Example 5 from3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and sulfapyridine.Electrospray MS 393 (MH⁺).

EXAMPLE 4 Preparation ofN-(5-methyl-1,3,4-thiadiazol-2-yl)-4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

The title compound was prepared analogous to Example 5 from3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and4-amino-N-(5-methyl[1,3,4]thiadiazol-2-yl)-benzenesulfonamide. ¹H NMR(DMSO) 13.90 (bs, 1H); 10.84 (d, 1H); 10.58 (s, 1H); 8.62 (d, 1H); 7.81(d, 2H); 7.60 (d, 1H); 7.55 (d, 2H); 7.12 (m, 1H); 6.95 (m, 1H); 7.84(d, 1H); 2.48 (s, 3H). Electrospray MS 414 (MH⁺).

EXAMPLE 5 Preparation of3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide

A mixture of 0.161 g (1.0 mmol) of(3Z)-3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one^(1,2) and0.180 g(1.05 mmol) of 3-aminobenzene-1-sulfonamide in 5 ml of EtOH was heatedto 80° C. for 45 min. After cooling to ambient temperature, the solidwas collected by vacuum filtration and air dried to afford3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-methyl]amino}benzenesulfonamideas a yellow solid (0.25 g, 79%). mp>250° C.; ¹H NMR (DMSO-d₆): 6.82 (d,J=7.7 Hz, 1H), 6.87-6.94 (m, 1H), 6.97-7.30 (m,1H), 7.35 (s, 2H),7.42-7.47 (m, 1H), 7.50-7.63 (m, 3H), 7.75 (t, J=1.8 Hz, 1H), 8.59 (d,J=12.1 Hz, 1H), 10.53 (s, 1H), 10.85 (d, J=12.3 Hz, 1H); APCI-MS: m/z316 (m+H)⁺. Anal. Calcd for C₁₅H₁₃N₃O₃S: C, 57.13; H, 4.16; N, 13.32; S,10.17. Found: C, 57.01; H, 4.23; N, 13.30; S, 10.11.

-   (1) Wolfbeis, Otto S.; Junek, Hans. Diacylenamines and -enoles, III.    Formylation of CH2-acidic compounds via the anilinomethylene    derivatives. Z. Naturforsch., B: Anorg. Chem., Org. Chem. (1979),    34B(2), 283-9 (2) Winn, Martin; Kyncl, John J. Aminomethylene    oxindoles. U.S. (1979), 6 pp. U.S. Pat. No. 4,145,422

Note: One equivalent of strong acid, e.g., HCl or methanesulfonic acid,is generally required in this reaction. The acid can be supplied as theaniline salt or as a separate component. Similar conditions can be usedfor condensing anilines with 3-dimethylaminomethylene-,3-t-butoxymethylene-, and 3-hydroxymethylene-substituted2,3-dihydro-1H-indol-2-ones.

Biological Data

The compounds of the present invention have valuable pharmacologicproperties. Different compounds from this class are particularlyeffective at inhibiting the trkA kinase enzyme at concentrations whichrange from 0.0001 to 1 μM and additionally show specificity relative toother kinases. Substrate phosphorylation assays were carried out asfollows:

Screening format: Tyrosine kinase activity is being measured using asynthetic peptide substrate. The enzyme is a GST-fusion of theintracellular domain expressed in SF9 cells. The enzyme is expressed andpurified by Regeneron. The enzyme is preincubated with cold ATP and Mgto allow autophosphorylation prior to running the screen. This increasesthe initial rate of catalysis approximately 3 fold. The assay isperformed in 96 well microtitre plates, and reaction products aredetected following filtration through millipore p81 phosphocelluloseplates.Assay Conditions

Peptide substrate Src peptide, NH2-RRRAAAEEIYGEI-NH2 Peptide Km 60 uMATP Km 30 uM Kcat/Km (peptide): 1 × 10⁴ Assay conditions 20-40 nM TrkA,30 uM ATP, 50 uM Src peptide, 50 mM MOPS pH 7.5, 10 mM MgCl², 0.6 uCi³³P

ATP Incubation RT for 120′ Termination Add 100 ul of 0.5% Phosphoricacid. Spot 100 ul onto millipore p81 96 well filter plate. Filter, wash3× with 200 ul 0.5% phosphoric acid. Add 50 ul scintillation cocktail.Count in Packard Topcount

Representative results are shown in Table 1 for the TrkA tyrosine kinaseinhibition

TABLE 1 Substrate Phosphorylation Example TrkA 1 +++ 2 +++ 3 ++ 4 ++ 5++ IC₅₀ values Symbol <0.010 uM +++ 0.010-0.10 uM ++ 0.10-1.0 uM + >1.0uM − Not determined ND

Utility of Invention

Inhibitors of members of the TrK family of kinases find utility asagents in the treatment of a wide variety of disorders. These includecancers and pain.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferreddosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for cancerconditions, or for other indications for the compounds of the inventionas indicated above. Likewise, the specific pharmacologic responsesobserved may vary according to and depending upon the particular activecompound selected or whether there are present certain pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvenion. It is intended, therefore, that the invention be limited onlyby the scope of the claims which follow and that such claims beinterpreted as broadly as is reasonable.

1. A compound of the formula I:

or salts, solvates, thereof wherein: R¹ is hydrogen; R² is hydrogen; R³is hydrogen; R⁴ is selected from the group consisting of4′-CH₂—SO₂NHCH₃, 4′-NHSO₂CH₃,

R⁵ is hydrogen; and X is N or CH.
 2. A compound as claimed in claim 1,wherein R¹, R², R³, and R⁵ —H, R⁴ is 4′-NHSO₂CH₃, and X is CH.
 3. Acompound as claimed in claim 1, wherein R¹, R², R³, and R⁵ are -H, R⁴ is

and X is CH.
 4. A compound as claimed in claim 1, wherein R¹, R², R³,and R⁵ are -H, R⁴ is

and X is CH.
 5. A compound as claimed in claim 1, wherein X is CH.
 6. Acompound selected from the group:{4-[(2Z)-2-(4-chloro-5-hydroxy-6-isopropyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]phenyl}-N-methylmethanesulfonamide;N-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)methanesulfonamide;4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}-N-(2-pyridinyl)benzenesulfonamide;N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}benzenesulfonamide;and salts, solvates thereof.
 7. A pharmaceutical composition,comprising: a therapeutically effective amount of a compound as claim 1,or a salt, or solvate, thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.
 8. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound as claim 6, or a salt, or solvate, thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.
 9. Acompound of the formula


10. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound as claim 9, or a salt, or solvate,thereof and one or more of pharmaceutically acceptable carriers,diluents and excipients.